Modulation of AMPA receptor‐mediated ion current by pituitary adenylate cyclase‐activating polypeptide (PACAP) in CA1 pyramidal neurons from rat hippocampus

Abstract

Pituitary adenylate cyclase-activating polypeptide (PACAP), a neurotrophic and neuromodulatory peptide, was recently shown to enhance NMDA receptor-mediated currents in the hippocampus (Macdonald, et al. 2005. J Neurosci 25:11374-11384). To check if PACAP might also modulate AMPA receptor function, we tested its effects on AMPA receptor-mediated synaptic currents on CA1 pyramidal neurons, using the patch clamp technique on hippocampal slices. In the presence of the NMDA antagonist D-AP5, PACAP (10 nM) reduced the amplitude of excitatory postsynaptic currents (EPSCs) evoked in CA1 pyramidal neurons by stimulation of Schaffer collaterals. Following a paired-pulse stimulation protocol, the paired-pulse ratio was unaffected in most neurons, suggesting that the AMPA-mediated EPSC was modulated by PACAP mainly at a postsynaptic level. PACAP also modulated the currents induced on CA1 pyramidal neurons by applications of either glutamate or AMPA. The effects of PACAP were dose-dependent: at a 0.5 nM dose, PACAP increased AMPA-mediated current; such effect was blocked by PACAP 6-38, a selective antagonist of PAC1 receptors. The enhancement of AMPA-mediated current by PACAP 0.5 nM was abolished when cAMPS-Rp, a PKA inhibitor, was added to the intracellular solution. At a 10 nM concentration, PACAP reduced AMPA-mediated current; such effect was not blocked by PACAP 6-38. The inhibitory effect of 10 nM PACAP was mimicked by Bay 55-9837 (a selective agonist of VPAC2 receptors), persisted in the presence of intracellular BAPTA and was abolished by intracellular cAMPS-Rp. Stimulation-evoked EPSCs in CA1 neurons were significantly reduced following application of the PAC1 antagonist PACAP 6-38; this result indicates that PAC1 receptors in the CA1 region are tonically activated by endogenous PACAP and enhance CA3-CA1 synaptic transmission. Our results show that PACAP differentially modulates AMPA receptor-mediated current in CA1 pyramidal neurons by activation of PAC1 and VPAC2 receptors, both involving the cAMP/PKA pathway; the functional significance will be discussed in light of the multiple effects exerted by PACAP on the CA3-CA1 synapse at different levels.

Regulation of AMPA receptor phosphorylation by the neuropeptide PACAP38

“…These findings offer a potential mechanism by which PACAP38 may regulate CA1 synaptic transmission. PACAP38 has been found to have a dose-dependent effect on CA1 synaptic transmission, where lower doses of PACAP38 enhance synaptic transmission and AMPAR EPSCs (20,24), and high doses reduce synaptic transmission and AMPAR EPSCs (20,24). Although it is unclear how this dose-dependent effect would occur, our data indicates that PACAP38-dependent changes in GluA1 phosphorylation could be a contributing factor that modulates synaptic transmission.…”

“…Maxadillan and (Lys15, Arg16,Leu27)-VIP(1-7)-GRF (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27), abbreviated as K,R,L-VIP-GRF, were purchased from Bachem. PACAP38, Bay 55-9837, Go6983, D-APV, and H89 were purchased from Tocris.…”

“…PACAP38 can bind to and activate three different G protein coupled receptors, the PAC1, VPAC1, and VPAC2 receptors, which can lead to elevated cyclic AMP and Ca 2+ levels, and activation of phospholipase C and phospholipase D (23). In the hippocampus, PACAP38 stimulation has been shown to alter synaptic strength (19)(20)(21)(22) and AMPAR excitatory postsynaptic currents (EPSCs) (24) and to reduce GluA1 synaptic localization (25). PACAP knockout mice are impaired in contextual fear conditioning and novel object recognition (26), and PAC1 receptor knockouts exhibit impaired contextual fear conditioning (27).…”

Pituitary Adenylate Cyclase-Activating Polypeptide and Its Receptors: 20 Years after the Discovery

“…PACAP contributes to synaptic transmission by enhancing NMDA receptor (Macdonald et al, 2005;MacDonald et al, 2007;Yang et al, 2009), increasing electrical activity (Di Mauro et al, 2003), and modulating AMPA receptor (Costa et al, 2009) in the hippocampus. PACAP has been shown to promote differentiation of embryonic stem cells into neurons and differentiation of neural stem cells into astrocytes (Vallejo and Vallejo, 2002;Cazillis et al, 2004;Ohno et al, 2005;Chafai et al, 2006;Hirose et al, 2006;Watanabe et al, 2006;Nishimoto et al, 2007).…”

The neuropeptide PACAP38 induces dendritic spine remodeling through ADAM10/N-Cadherin signaling pathway

“…A recent study showed that treatment with PACAP38 at a very low concentration reduced a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor excitatory postsynaptic currents (EPSCs) through PAC1-receptor independent signaling (Costa et al 2009). By contrast, another study showed that the application of PACAP38 enhanced AMPA-evoked currents (Michel et al, 2006).…”